Mecillinam.html |
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Mecillinam
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| Systematic (IUPAC) name | |
| (2S,5R,6R)-6-(azepan-1-ylmethylideneamino)-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | |
| Identifiers | |
| CAS number | 32886-97-8 (pivmecillinam) |
| ATC code | J01 J01 (pivmecillinam) |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C15H23N3O3S |
| Mol. mass | 325.426 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | Negligible (mecillinam) Low (pivmecillinam) |
| Protein binding | 5 to 10% |
| Metabolism | Some hepatic metabolism. Pivmecillinam is hydrolyzed to mecillinam |
| Half life | 1 to 3 hours |
| Excretion | Renal and biliary, mostly unchanged |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
℞ Prescription only |
| Routes | Intravenous, intramuscular Pivmecillinam is given orally |
Mecillinam (INN) or amdinocillin (USAN), trade name Coactin, is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 (PBP2),2 and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever.345 Because mecillinam has very low oral bioavailability, an orally-active prodrug was developed: pivmecillinam or amdinocillin pivoxil (trade names Selexid and Coactabs), the pivaloyloxymethyl ester of mecillinam. Neither drug is available in the United States.6
In the Nordic countries, pivmecillinam has been widely used to treat lower urinary tract infections since the 1970s. It has been proposed as the first-line drug of choice for empirical treatment of acute cystitis.71
Contents |
History
With the codename FL 1060, mecillinam was developed by the Danish pharmaceutical company Leo Pharmaceutical Products (now LEO Pharma). It was first described in the scientific literature in a 1972 paper.89
Activity
Mecillinam is active against most pathogenic Gram-negative bacteria, except Pseudomonas aeruginosa and some species of Proteus.6 Several studies have also found it to be as effective as other antibiotics for treating Staphylococcus saprophyticus infection, even though it is Gram-positive, possibly because mecillinam reaches very high concentrations in urine.1
Worldwide resistance to mecillinam in bacteria causing urinary tract infection has remained very low since its introduction; a 2003 study conducted in 16 European countries and Canada found resistance to range between 1.2% (Escherichia coli) to 5.2% (Proteus mirabilis).10 Another large study conducted in Europe and Brazil obtained similar results—95.9% of E. coli strains, for instance, were sensitive to mecillinam.11
Adverse effects
- See also: Beta-lactam antibiotic: Adverse effects
The adverse effect profile of mecillinam is similar to that of other penicillins.2 The most common side effects of mecillinam use are rash and gastrointestinal upset, including nausea and vomiting.112
Prodrugs that release pivalic acid when broken down by the body—such as pivmecillinam, pivampicillin and cefditoren pivoxil—have long been known to deplete levels of carnitine.1314 This is not due to the drug itself, but to pivalate, which is mostly removed from the body by forming a conjugate with carnitine. Although short-term use of these drugs can cause a marked decrease in blood levels of carnitine,15 it is unlikely to be of clinical significance;14 long-term use, however, appears problematic and is not recommended.161417
References
- ^ a b c d Nicolle LE (August 2000). "Pivmecillinam in the treatment of urinary tract infections". J Antimicrob Chemother 46 Suppl A: 35–39. PMID 10969050, http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10969050.
- ^ a b Neu HC (1985). "Amdinocillin: a novel penicillin. Antibacterial activity, pharmacology and clinical use". Pharmacotherapy 5 (1): 1–10. PMID 3885172.
- ^ Clarke PD, Geddes AM, McGhie D, Wall JC (July 1976). "Mecillinam: a new antibiotic for enteric fever". Br Med J 2 (6026): 14–5. PMID 820402.
- ^ Geddes AM, Clarke PD (July 1977). "The treatment of enteric fever with mecillinam". J Antimicrob Chemother 3 Suppl B: 101–2. PMID 408321.
- ^ Tanphaichitra D, Srimuang S, Chiaprasittigul P, Menday P, Christensen OE (1984). "The combination of pivmecillinam and pivampicillin in the treatment of enteric fever". Infection 12 (6): 381–3. PMID 6569851.
- ^ a b Pham P, Bartlett JG (August 28, 2008). "Amdinocillin (Mecillinam)". Point-of-Care Information Technology ABX Guide. Johns Hopkins University. Retrieved on August 31, 2008. Freely available with registration.
- ^ Graninger W (October 2003). "Pivmecillinam—therapy of choice for lower urinary tract infection". Int J Antimicrob Agents 22 Suppl 2: 73–8. PMID 14527775, http://linkinghub.elsevier.com/retrieve/pii/S0924857903002358.
- ^ Lund F, Tybring L (April 1972). "6β-amidinopenicillanic acids—a new group of antibiotics". Nature New Biol 236 (66): 135–7. PMID 4402006.
- ^ Tybring L, Melchior NH (September 1975). "Mecillinam (FL 1060), a 6β-amidinopenicillanic acid derivative: bactericidal action and synergy in vitro". Antimicrob Agents Chemother 8 (3): 271–6. PMID 170856. PMC: 429305, http://aac.asm.org/cgi/pmidlookup?view=long&pmid=170856.
- ^ Kahlmeter G (January 2003). "An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO·SENS Project". J Antimicrob Chemother 51 (1): 69–76. PMID 12493789, http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12493789.
- ^ Naber KG, Schito G, Botto H, Palou J, Mazzei T (May 2008). "Surveillance Study in Europe and Brazil on Clinical Aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): Implications for Empiric Therapy". Eur Urol. doi:. PMID 18511178.
- ^ "Selexid Tablets". electronic Medicines Compendium (June 5, 2008). Retrieved on August 31, 2008.
- ^ Holme E, Greter J, Jacobson CE, et al (August 1989). "Carnitine deficiency induced by pivampicillin and pivmecillinam therapy". Lancet 2 (8661): 469–73. PMID 2570185, http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(89)92086-2.
- ^ a b c Brass EP (December 2002). "Pivalate-generating prodrugs and carnitine homeostasis in man". Pharmacol Rev 54 (4): 589–98. PMID 12429869, http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12429869.
- ^ Abrahamsson K, Holme E, Jodal U, Lindstedt S, Nordin I (June 1995). "Effect of short-term treatment with pivalic acid containing antibiotics on serum carnitine concentration—a risk irrespective of age". Biochem. Mol. Med. 55 (1): 77–9. PMID 7551831, http://linkinghub.elsevier.com/retrieve/pii/S1077315085710368.
- ^ Holme E, Jodal U, Linstedt S, Nordin I (September 1992). "Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children". Scand J Clin Lab Invest 52 (5): 361–72. PMID 1514015.
- ^ Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N (September 2007). "Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid". Pediatrics 120 (3): e739–41. doi:. PMID 17724113.